Nateglinide, known as (−)-N-(trans-4-isoporpylcyclohexanecarbonyl)-D-Phenylalanine, has the following structure and characteristics:
FormulaC19H27NO3Molecular Weight317.42Exact Mass317.199093CompositionC 71.89% H 8.57% N 4.41% O 15.12%Nateglinide is marketed as STARLIX, which is prescribed as oral tablets having a dosage of 60 mg and 120 mg for the treatment of type II diabetes. STARLIX may be used as monotherapy or in combination with metaformin to stimulate the pancreas to secrete insulin. According to the maker of STARLIX, nateglinide is a white powder that is freely soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water. Metabolites of nateglinide are disclosed in Hiroko Takesada, et al., Bioorg. Med. Chemical, 4(10) 1771-81 (1996).
U.S. Pat. No. 4,816,484 and its subsequent reissue (U.S. Re 34878) disclose nateglinide and a method for its preparation. The process of the '484 patent reacts a D-phenylalanine ester derivative with a DCC derivative of 4-isopropylcyclohexanecarboxylic acid, followed by de-esterification to obtain nateglinide, as illustrated below: 
The yield obtained is 65%.
The ester acts as a protecting group, limiting the amount of undesirable cross reactions. The process of U.S. Pat. No. 4,816,484 however may contaminate the final product with the methyl ester since removal of the ester as a protecting group would probably not be complete, leaving at least some minor amounts of the ester as an impurity in the final product. In addition, crystallization from aqueous methanol might result in esterification of the product.
A general problem with preparing nateglidine is the presence of the corresponding undesirable cis isomer during the process, which leads to a final product that is contaminated with the corresponding cis isomer. In order to increase the ratio of the therapeutically effective trans isomer over its corresponding cis isomer, the process of the '484 patent heats a cis-trans mixture of the methyl ester of 4-isopropylcyclohexane carboxylic acid in the presence of sodium hydride. A discussion of U.S. Pat. No. 4,816,484 may be found in Hisashi Shinkai, et. al., J. Med. Chem. 32(7) 1436-1441 (1989).
A Chinese article discloses another reaction scheme for preparing nateglinide, in which the cis to trans ratio of isopropyl cyclohexylcarboxylic acid is decreased by treatment with KOH in methanol at elevated temperatures. Xue-yan Zhu, et. al., Hecheng Huaxue 9(6) 537-540 (2001) (hereinafter “Xue-yan Zhu”). The reaction uses phosphorus pentachloride (“PCl5”) to chlorinate isopropylcyclohexane carboxylic acid, to obtain an acid chloride, which is then reacted with D-phenylalanine to obtain nateglinide. The reaction has the following scheme, which may result in contamination of the final product with nateglinide's corresponding cis impurity: 
Another article discloses a process for preparing the trans isomer of 4-isopropylcyclohexane carbonyl chloride (syn. of 4-isopropylcyclohexane acid chloride (“IPCHAC”) by chlorination of 4-isopropylcyclohexanecarboxylic acid with PCl5 [Jpn. Kokai Tokkyo Kohop (1995) (hereinafter “Kokai”)]. Kokai and a Japanese patent, JP 070107899A, disclose that use of thionyl chloride leads to formation of the corresponding cis isomer.
In addition to the above references, nateglinide is also disclosed in U.S. Pat. Nos. 5,463,116 and 5,488,150, and three Japanese publications: WO 02/34254, WO 02/34285 and WO 02/34713. All of these references are incorporated herein by reference.
There is a need in the art for additional processes for preparing nateglinide.